1-hydroxyalkylidene-1,1-biphosphonic acids of the general formula (1)
including salts and hydrates thereof, represent an important class of pharmaceuticals, useful for treatment or prevention of osteoporosis. In the general formula (1), the Z represents a methyl group or a substituted methyl group, particularly substituted by a nitrogen-containing substituent. More particularly, the biphosphonic acids listed below have been the subject of considerable research efforts and many of them are marketed as pharmaceutically active compounds in various pharmaceutical compositions, mostly as hydrated sodium salts:
etidronic acidZ = methylpamidronic acidZ = 2-aminoethylalendronic acidZ = 3-aminopropylneridronic acidZ = 5-aminopentylolpadronic acidZ = 2-(N,N-dimethylamino)ethylibandronic acidZ = 2-(N-methyl-N-pentylamino)ethylrisedronic acidZ = pyridin-3-ylmethylzoledronic acidZ = 2-imidazol-1-ylmethylminodronic acidZ = (imidazo[1,2a]pyridin-2yl)methyl
In a known general process for making the compounds of formula (1), an acid of the general formula (2)Z—COOH  (2)is reacted in a solvent (or in a diluent) and at an enhanced temperature with a phosphonation agent, which may be a mixture of phosphorous acid and a halophosphorous compound (such as phosphorous trichloride PCl3, phosphorous pentachloride PCl5, phosphorous oxychloride POCl3, and the like), and the resulting complex mixture of cyclic pyrophosphonate intermediates (the nature of which has been suggested, e.g., in U.S. Pat. No. 5,510,517) is hydrolyzed by heating the mixture with water or a non-oxidizing aqueous acid to form a biphosphonic acid. The obtained biphosphonic acid is then optionally isolated, or is optionally converted into a corresponding salt and then isolated.
There are many prior art documents dealing with this general process. Many of the used diluents do not fully dissolve the reaction components (e.g., the compound of formula (2) and/or the phosphonation agent), so that the resulting reaction mixture is a poorly stirred polyphasic mass, the work-up of which is quite complicated. See, e.g., U.S. Pat. No. 4,407,761, wherein the reaction proceeds in chlorobenzene, U.S. Pat. No. 7,038,083, wherein the diluent is an aromatic hydrocarbon, US 2006/0258625, which used diphenyl ether, or WO 2007/083240, which used a phenolic compound as a diluent. Solubilization may be achieved in some cases by using methane sulfonic acid (U.S. Pat. No. 4,922,007 and U.S. Pat. No. 5,019,651), polyalkylene glycols (U.S. Pat. No. 5,908,959, WO 98/34940), triglycerides or alkyl/aralkyl ethoxylates (WO 02/090367), however, these solubilization agents complicate the elaboration of the reaction mixture as well.
In general, the main problems in the known synthetic process are high viscosity and, in some embodiments, polyphasic character of the reaction mixture comprising the cyclic pyrophosphonate intermediates which leads to poor heat transfer and problems with subsequent work-up; use of high boiling solvents/diluents that may be difficult to remove from the reaction mixture or from the isolated product; and formation of side products arising from the excess of the phosphonation agents. These disadvantages are manifested, in particular, in a large scale production.
Thus, there is a need to improve the conditions of reaction between the compound of formula (2) and the phosphonation agent yielding the biphosphonates of the formula (1). In particular, there is a need to find a solvent/diluent, which is readily available, does not cause solidification of the reaction mixture, and can be easily removed from the product.